L-Arginine and intestinal barrier function

L-Arginine (L-Arg) is a semi-essential amino acid. Basal requirements of L-Arginine can be met through endogenous synthesis in the body, but exogenous supplementation is necessary under special conditions such as stress, infection, and intestinal injury. Its regulatory effect on intestinal barrier function stems from multi-targeted modulation of intestinal mucosal cell proliferation, tight junction integrity, immune-inflammatory balance, and gut microbiota. As a key nutrient for maintaining intestinal barrier homeostasis and repairing mucosal damage,L-Arginine holds significant value in clinical nutritional support and intestinal disease intervention.

I. Core Mechanisms Regulating Intestinal Barrier Function

The intestinal barrier consists of four layers: the mechanical barrier, chemical barrier, immune barrier, and biological barrier.L-Arginine exerts functional enhancement and damage repair effects on each layer through distinct pathways.

Preserving the Intestinal Mechanical Barrier: Promoting Mucosal Proliferation and Tight Junction StabilityThe intestinal mechanical barrier, a physical defense composed of intestinal epithelial cells and intercellular tight junctions (TJs), serves as the core line of defense against the invasion of intestinal toxins and antigens.

Promoting Intestinal Mucosal Cell Proliferation and Survival

L-Arginine acts as a primary energy substrate and synthetic precursor for intestinal epithelial cells. By activating the mTOR signaling pathway, it stimulates protein synthesis, proliferation, and differentiation of intestinal mucosal cells (e.g., intestinal villus columnar epithelial cells, crypt stem cells), accelerates villus repair, increases the villus height-to-crypt depth ratio, and enhances mucosal structural integrity. Meanwhile, polyamines (putrescine, spermidine, spermine) derived from L-Arginine metabolism are key regulators of cell proliferation; they inhibit intestinal epithelial cell apoptosis and reduce cell shedding following mucosal injury.

Enhancing Tight Junction Integrity

The expression and distribution of intercellular tight junction proteins (e.g., occludin, claudin, ZO-1) directly determine mechanical barrier permeability.L-Arginine stabilizes tight junctions via two pathways: first, as a substrate for nitric oxide synthase (NOS), it generates nitric oxide (NO), which dilates intestinal mucosal blood vessels, improves mucosal blood supply, and provides sufficient oxygen and nutrients for tight junction protein synthesis; second, it inhibits tight junction protein degradation mediated by pro-inflammatory factors (e.g., TNF-α, IL-6), preventing the enlargement of intestinal epithelial cell gaps and reducing intestinal permeability.

Modulating the Intestinal Immune Barrier: Balancing Inflammatory Responses and Mucosal ImmunityThe intestinal immune barrier is centered on immune cells in the intestinal mucosal lamina propria (macrophages, dendritic cells, lymphocytes) and secretory immunoglobulin A (sIgA).L-Arginine maintains intestinal immune homeostasis by regulating immune cell functions.

Dual Anti-inflammatory Effects Mediated by NO and Polyamines

High levels of NO produced by L-Arginine catalyzed by inducible nitric oxide synthase (iNOS) exert antibacterial and antiviral effects in the early stage of infection; however, excessive NO can induce oxidative stress and damage the intestinal mucosa. At physiological concentrations,L-Arginine preferentially activates constitutive nitric oxide synthase (cNOS) to generate low levels of NO, which ensures mucosal blood supply while avoiding inflammatory damage. Additionally, polyamines from L-Arginine metabolism inhibit the activation of the nuclear factor κB (NF-κB) pathway, reduce pro-inflammatory factor release, and alleviate intestinal mucosal inflammation.

Promoting sIgA Secretion and Immune Cell Differentiation

L-Arginine stimulates sIgA secretion by plasma cells in the intestinal lamina propria. sIgA can encapsulate intestinal pathogenic bacteria and antigens, prevent their adhesion to intestinal epithelial cells, and strengthen the function of the chemical barrier. Furthermore,L-Arginine promotes dendritic cell maturation and regulatory T cell (Treg) differentiation, inhibits excessive immune responses, and reduces barrier damage caused by intestinal inflammation.

Optimizing the Intestinal Biological Barrier: Regulating Gut Microbiota StructureThe intestinal biological barrier is composed of commensal microbiota, and its balanced state is closely linked to intestinal barrier function.L-Arginine serves as a nutritional substrate for beneficial bacteria (e.g., Lactobacillus, Bifidobacterium), promoting their proliferation and increasing their proportion in the gut microbiota. Simultaneously, it inhibits the growth and reproduction of pathogenic bacteria (e.g., Escherichia coli, Salmonella), reducing the stimulation of intestinal mucosa by endotoxins produced by pathogens.The proliferation of beneficial bacteria leads to the production of short-chain fatty acids (SCFAs), which provide energy for intestinal epithelial cells and further enhance intestinal barrier function, forming a positive regulatory cycle of L-Arg – beneficial bacteria – SCFAs.

Improving Intestinal Microcirculation: Ensuring Mucosal Nutrient SupplyNO generated by L-Arginine catalyzed by cNOS is a potent vasodilator; it dilates intestinal mucosal microvessels, increases mucosal blood flow, and ameliorates intestinal mucosal ischemia and hypoxia. Under pathological conditions such as shock and inflammatory bowel disease, intestinal mucosal ischemia is a major contributor to barrier damage.L-Arginine supplementation can reverse mucosal ischemia and promote barrier repair through NO-mediated microcirculation improvement.

II. Clinical Applications in Intestinal-related Diseases

Based on its regulatory role in the intestinal barrier,L-Arginine has been widely used in nutritional support and adjuvant therapy for clinical intestinal diseases. The core application scenarios are as follows:

Inflammatory Bowel Disease (IBD): Ulcerative Colitis and Crohn’s DiseaseThe core pathological features of IBD include chronic intestinal mucosal inflammation, barrier disruption, and increased permeability.

Clinical Evidence: Multiple clinical studies have shown that supplementing active-stage IBD patients with L-Arginine (3–6 g orally daily) can significantly reduce fecal levels of intestinal mucosal injury markers (e.g., lactoferrin, calprotectin), increase serum indicators related to tight junction proteins, and alleviate diarrhea and abdominal pain symptoms.

Mechanism of Application: It reduces pro-inflammatory factor release by inhibiting the NF-κB pathway, repairs the intestinal mucosal mechanical barrier, regulates gut microbiota balance, and mitigates persistent barrier damage caused by intestinal inflammation.

Precautions: High-dose use (> 10 g/day) should be avoided. Excessive L-Arginine may induce the production of large amounts of NO via iNOS, exacerbating inflammatory responses and oxidative stress.

Intestinal Mucosal Ischemia-reperfusion Injury: Shock and Surgery-related InjuryShock (e.g., septic shock, hemorrhagic shock) or abdominal surgeries (e.g., intestinal resection, transplantation) are prone to induce intestinal mucosal ischemia-reperfusion injury, leading to intestinal barrier dysfunction and even systemic inflammatory response syndrome (SIRS).

Clinical Application: Supplementing L-Arginine via enteral nutrition (0.2–0.5 g/kg daily) during the perioperative period or shock resuscitation phase can significantly improve intestinal mucosal microcirculation, reduce intestinal permeability, decrease endotoxin translocation into the bloodstream, and lower the incidence of SIRS.

Advantages: Compared with simple fluid replacement,L-Arginine repairs intestinal mucosa at the cellular level and improves resuscitation quality, making it particularly suitable for intestinal protection in critically ill patients.

Necrotizing Enterocolitis (NEC) in NeonatesNeonates, especially premature infants, have underdeveloped intestinal barriers and are susceptible to NEC, whose pathological basis involves intestinal mucosal ischemia, inflammation, and barrier disruption.

Clinical Value: Adding L-Arginine (0.1–0.3 g/kg daily) to early enteral nutrition for high-risk premature infants can promote intestinal mucosal cell proliferation, enhance tight junction stability, and reduce the incidence of NEC. Clinical studies indicate that the NEC incidence rate in premature infants supplemented with L-Arg is 30%–40% lower than that in the control group.

Application Principles: L-Arginine should be gradually added within the range of intestinal tolerance in neonates to avoid intestinal irritation caused by high concentrations.

Irritable Bowel Syndrome (IBS)IBS patients exhibit increased intestinal barrier permeability, immune dysfunction, and microbiota imbalance, manifested as alternating abdominal pain, diarrhea, or constipation.

Clinical Efficacy: Oral administration of L-Arginine (2–4 g daily) can reduce intestinal permeability, regulate gut microbiota structure, alleviate intestinal hypersensitivity and inflammatory responses, and relieve IBS-related symptoms. Its mechanism of action is closely associated with tight junction repair and sIgA secretion promotion.

Clinical Nutritional Support: Tumors and Chronic Wasting DiseasesAfter radiotherapy and chemotherapy, tumor patients or those with chronic wasting diseases often experience intestinal barrier dysfunction due to malnutrition, leading to impaired absorption and increased infection risk.

Application Scheme: Adding L-Arginine (accounting for 2%–5% of total amino acids) to enteral nutrition preparations can improve the intestinal mucosal nutritional status of patients, repair barrier function, enhance nutrient absorption rate, boost immune function, and reduce the risk of infectious complications.

III. Precautions and Challenges in Clinical Application

Dose Dependence and Individual DifferencesThe effects of L-Arginine are dose-dependent. Physiological doses (0.2–0.5 g/kg daily) can repair the intestinal barrier, while excessive doses may trigger adverse reactions. In addition, L-Arginine requirements vary among patients with different disease states, necessitating individualized dose adjustment.

Contraindications and Cautious Populations

Cautious use in patients with severe hepatic or renal insufficiency: Urea produced by L-Arg metabolism is excreted through the liver and kidneys. Hepatic and renal dysfunction may lead to elevated blood ammonia levels and induce hepatic encephalopathy.

Cautious use in patients with bleeding tendency: NO inhibits platelet aggregation, which may increase the risk of bleeding.

Combination Therapy StrategiesCombined use of L-Arginine with glutamine, short-chain fatty acids, probiotics, etc., can exert synergistic effects and enhance intestinal barrier repair efficacy. For example, glutamine provides energy for intestinal epithelial cells, probiotics optimize microbiota structure, and their combination with L-Arginine achieves multi-targeted regulation.

L-Arginine achieves precise regulation of intestinal barrier function through multiple pathways, including promoting intestinal mucosal proliferation, stabilizing tight junctions, balancing immune inflammation, and regulating gut microbiota. It has demonstrated significant value in the clinical intervention of diseases such as inflammatory bowel disease, intestinal ischemia-reperfusion injury, and neonatal NEC. Future research should focus on large-sample, multi-center clinical trials to clarify the optimal dosage, administration route, and treatment course for different diseases, while exploring synergistic regimens of L-Arginine with other nutrients and drugs, thereby providing more precise strategies for the clinical treatment of intestinal barrier dysfunction.